Process for the preparation of dichloracetamido propanes



United States Patent PROCESS FOR THE PREPARATION OF DICHLORACETAMIDO PROPANES Basil Jason Heywood, Romford, England, assignor, by

mesne assignments, to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Application May 14, 1951 Serial No. 226,290

Claims priority, application Great Britain May 19, 1 95 7 Claims. (Cl. 260-562) This present invention relates to the preparation of dichloracetamides and is particularly concerned with the preparation of N-dichloracetyl derivatives of the general formula:

mO-gn-pn-omom R1 NHCOCHCI: I in which:

R1 and R2 are the same or are difierent, each representing a hydrogen atom or a lower alkyl or aralkyl group or together constituting a divalent atom or group of atoms joining the two oxygen atoms such as CO--, or CHR4-- where R4 represents a hydrogen atom or a lower alkyl, cycloalkyl, aryl or aralkyl group and R3 represents a hydrogen atom or a nitro group. In a preferred form of this invention, R1 and R2 each represent a hydrogen atom.

- Various processes have heretofore been employed for the preparation of certain of these compounds; thus, for example, the acid chloride, anhydride, or esters of dichloracetic acid are known to react with the appropriate amines to give compounds of type I in which R1 and'Rz represent hydrogen atoms.

It is the object of the present invention to provide improved syntheses of the aforesaid compounds which offer commercial advantage over those hitherto employed.

In accordance with this invention, the N-dichloracetyl derivatives of type I are prepared by reacting the corresponding amines of the type:

R NH: II

with chloral cyanhydrin, or precursor therefor, in the presence of an acid-binding agent. If desired, the chloral cyanhydrin may first be treated with an acid-binding agent and the reaction product so-obtained used as the di chloracetylating agent.

In accordance with a feature of this invention, an especially convenient precursor for chloral cyanhydrin consists of chloral, or chloral hydrate, in the presence of an alkali metal cyanide catalyst, the catalyst being pref- I erably employed in quantity less than one molecular equivalent of the reacting amine. j

In carrying the present invention into elTect, the acidbinding agent used may be an inorganic or a tertiary or ganic base or an excess of the reacting amine or, when such is to be present in the reaction mixture as catalyst, an excess of alkali metal cyanide catalyst; The preferred acid-binding agents are strong tertiary organic bases such as triethylamine when chloral cyanhydrin is employed directly as the dichlorac'etylating agent, whereas when chloral or chloral hydrate is used inorganic bases such as precipitated calcium carbonate, magnesium oxide and sodium carbonate have been found to be most advanta- The reaction medium may be aqueous or non-aqueous and, of organic solvents, both dioxari and pyridine have ice.

2,718,527 Patented Sept.-- 20, 1955 been found to be very suitable, the preferred reaction medium when chloral or chloral hydrate is employed being water and, when chloral cyanhydrin is employed, dioxan.

When chloral cyanhydrin is employed as such, the reaction is preferably efiected at a temperature of 0-25 C. while, when chloral or chloral hydrate is employed in the presence of cyanide catalyst, it is preferred to increase the reaction temperature to 60l00 C.

In addition to the high degree of purity and the excellent yields in which the products are obtained, a further advantage of the process of the present invention is that, using chloral cyanhydrin direct, the reaction proceedsat normal temperatures thus enabling simpler procedures to be used than those of the methods previously employed.

The products of this invention can be regarded-as comprising the compounds of type III and those of type IV 0R1 NHO OCHCI:

III

NHCOCHC]:

in which R and R are separate radicals hereinbefore defined (preferably hydrogen atoms) and Y represents the case where R1 and R2 in general formula I together constitute a divalent atom or group. These compounds, like the amines from which they are prepared, each contain two asymmetric carbon atoms and can exist in structural as well as optical isomeric forms. The term structuraP refers to the spatial relationship of the polar groups respectively attached to the two asymmetric carbon atoms. In conformity with the nomenclature adopted by M. C. Rebstock, H. M. Crooks, J. Controulis and Q. R. Bartz, L. H. Long and H. D. Troutman in the Journal of the American Chemical Society 1949, volume 71, pages 2458 to 2473, the diastereoisomeric forms are designated erythro and threo respectively.

Both the erythro and the threo forms can exist as racemates of optically active isomers whence it follows that each compound can exist in six different forms and, accordingly, a given structural formula of the conventional type as used herein, represents any of the forms, the racemates of the erythro and threo series and four il'ldl', vidual isomers, D-erythro, L-erythro, D-threo and L- threo or a mixture of two or more of these forms unless otherwise stated. v

An especially important feature of the present inven' tion consists in the production of DL- and L- erythro compounds of type III employing the corresponding amines of type II, which compounds of type III are valuable intermediates for the production of the therapeutically active D-threo 2-dichloracetamido-l-p-nitrophenylpropane 1:3-diol, commonly known as chloramphenicol and the DL-mixture containing the same. The compounds of type IV may be converted into those of type III by hydrolysis. I

The present invention is illustrated by the following examples.

- Example I To a stirred and refluxing mixture of DL-erythro 5- amino-4-phenyl-2-methyl-l:3-dioxan (19.5 g.) precipitated calcium carbonate,(l2.0 g.) sodium cyanide (0.95 g.) and water '(45 'cc.), asolution of chloral hydrate (25,4 g.) in water (10 cc.) was added cautiously over ten minutes. The reaction-mixture was stirred and refluxed for hydrochloricacid was added to the stirred reaction mix- 3 ture 'to render it aeidto Congo red. The DL-erythro Sadichloracetamido- 4 -phenyl --2 methyl -1:-3 -.-dioxan (25.5 g.) 85% of theory was filtered off and dried at 100 C. The amide may be crystallised from methanol whenitseparates in colourless crystals M. P.220222' C.

Example 11 Toia stirred mixture at 95- C. of DL-erythro S-amino- 4-iphenyl-2-methyl-1:3-dioxan (3.94 g.), dioxan cc.), water-(5- cc.) sodium cyanide (0.2 g.) and sodiumacetate crystals (4.5 g.) was added a solution of chloral hydrate (4.67 g.) in water (2'cc.) over 30seconds. The emulsion was. stirred 'at 95-100 C. for minutes and then seodod with crystals of the desired product, when the mass crystallised. The mixture was cooled to C., madeacid to Congo-red and the reaction product isolated. 'lheiproduct, DL=erythro 5-dichloracetamido-4phenyl-2- methilelzIl-dioxan, melted at=216-217 C. One crystallisation: of this product from methanol gave apureproduct, .melting-at-'224 C.

Example III In places of 19.5 .g. of DL-erythro'5 amino-4-phenyl- 2-methyl-1z3-dioxan used in Example I, 21.2 g. of DL- threo 2-amino-l-p-nitrophenylpropane 1:3-diol were employed. The "dichlor'acetyl derivative,-DL-threo 2-dichloracetamide-l-p-nitrophenylpropane 1:3-diol was filtered off as in Example I and a further quantity obtained by extraction of the aqueous filtrate with ethyl acetate and evaporation of the extract. The total yield was 28.1 g. which is 87% of theory. Crystallisation from a mixture'vof ethyl acetate and petroleum ether gave an almost eolourlessproductmelting at 150 C.

Example IV A mixture of .DL-erythro Z-amino-l-p-nitrophenylpropane 1:3-diol (0.53 g.), magnesium oxide (0.125 g.), sodium cyanide (0.05 g.) and water (2.5 cc.) was stirred and-heatedto the boiling point. Asolution of chloral hydrate (0.582 g.) in water (1 cc.) was added over minute and the reaction was allowed to stir and reflux for l0-minutes. The cooled reaction mixture was made-acid to Congo rcd'by the addition of hydrochloric acid and the crystalline product filtered off, washed with a little water and dried. The yield of DL-erythro Z-dichloracetamido-l-p-nitrophenylpropane 1:3-diol obtained was 65% theory.

Example V To-a-mechanically stirred solution at 40 C. of D1.- erythro 2 amino 1 -p nitrophenylpropane 1:3-diol ('0i53g.), sodium carbonate (anhydrous 0.325 g.), sodium cyanide (0.05 g.) and water (2.5cc.) was added-over %minute asolution of chloral hydrate (0.625 g.) inwater 1cc). The-product, DL-erythro Z-dichIoracetamido-I- p-nitrophenylpropane 1:3-diol, was isolated in the'sa'me w'a'yas described in Example IV.

Example VI The sodiumcyanide (0.05 g.) employed inExample V, was replaced by potassium cyanide (0.066 g), and gave the same reaction product.

Example VII and then the product isolated as decribed in Example -I-V. Theyield obtained of DL-erythro Z-dichloracetamido-l-p-nitro-phenylpropane 1:3-diol was 72% of theory.

Example IX To a stirred suspension of DL-erythro 2-amino-1-pnitrophenylpropane'l:3'-dio1 (0.53 g.), magnesium oxide (0.756 gl),sodiu'm cyanide (0.061 g.) and water at 40 .C. -was;- added over 10 minutes a solution of-chloral hydrate-(0:629) in"water .(1 cc.). The DL-erythro 2 dichloracetamido 1=p nitrophenylpropane 1:3-diol obtained was isolated as described in Example IV. The yield was 60%of theory. 7

The reaction can be carried out at C. with a slightly i'll'lproved :yield.

"Example X A- mixture of DL-threo -2ami1io-l-p nitrophenylpropaine 1z3-diol (2.12 g.) chloral hydrate-(2'.-20..g;) "dry pyridine (5- cc.) and sodium cyanide (0.7 g.) was heated on the steam bath for some hours. The solution 'was poured onto water and the precipitated solid filtered off and dried at 100 C. 'A-fter crystallisation from ethyl acetate-petroleum ether mixture, the DL-threo Z-dichloracetamido-l-p-nitrophenylpropane 1:3-diol so obtained melts at -l51 C. v

The reaction medium, pyridine, used in this example can befreplaced by dioxan 'with -a similarr'e'sult.

Example XI 2.5 g. t of 'DL-erythro '2'-amino l-p-nitrophenylpropane 1:-3-di'ol hydrochloride of MVP. (cap.) 208-211 C. were suspended in anhydrous dioxan (12 Co.) with anhydrous pyridine (1.9 "cc.). After cooling to 10 -C., chloral hydrate (2.56 g.) was added. The temperature rose to +15 C.,'an'dafter recooling to +8 C., 0.87 g. of sodium-cyanide (95% purity) was added; the temperature rose to "30" C. The'milky solution obtained was "agitated" for two hours atordinary temperature, then' diluted with distilled water- (40 'cc.) and left to stand for "one hour in an ice-bath. The product which crystallised was separated ofi, washed with water and dried in vacuo. A-crude-product (2.4 g.) of M. P. (cap.) -150l60 C. was obtainedwhichonrecrystallisation and decolou'risation with charcoal in boiling water (50 cc.) -gave DL- erythro 1 Z-dichloralctamido-l-p-nitrophenylpropane 1 :3- diol, M. P. (cap.) 169.5l70.5 C.

Example XII Chloral cyanhydrin (10.9 g.) Was'dissolved in dioxan (20 cc.) and cooled in an ice-water bath while DL- erythro 5-amino-4-phenyl-2-methyl-1:3-dioxan (9165 'g.) (M. P. 73-75 C.) was added over five minutes. To the cooled solution was added slowly triethylamine (10 g.). The almost solid suspension was allowed to stand at normal. temperature for 14 hours and then poured onto ice and water. After standing for-some time, the suspension was made acid to Congo red by the addition ofconce'ntrated hydrochloric acid and the solid was filtered off. The yield or DL-erythro 5-dichloracetamido 4- phenyl-2-methyl 1:3-dioxan was 90% of theory. After purification the melting point was 220-224" C. The product'isbelieved to have the formula:

hITHC OOHClz f5 w 0 O \v CH CH3 Example-XIII Chloral cyanhydrin (10.9 g.) was dissolved in dioxan (201cc) "and cool'ed'in an ice-waterbath while 'DL-thjreo.

131-131.5 C. This product is also represented by the same structural formula as shown in Example XII, although of course, they are difierent chemical compounds.

Example XIV DL-erythro amino 4 phenyl 2 methyl 1:3-

dioxan (1.93 g.) (M. P. 73-75 C.) was dissolved in 2 N hydrochloric acid (5 cc.) and water cc.). The solution was cooled to 0 C. and chloral cyanhydrin (2.25 g.) added. To this stirred and cooled solution was added 2 N sodium hydroxide over half an hour. The suspension was allowed to stand overnight when the crystalline solid-was filtered 01f, washed with water and dried. The yield (2.0 g.) of DL-erythro S-dichloracetamido-4-phenyl-2-methyl-1:3-dioxan was 66% of theory.

Example XV DL-threo 2-amino-1-p-nitrophenylpropane 1:3-diol (4.24 g.) was dissolved in pure hot dioxan (25 cc.) and the solution allowed to crystallise in an ice-water bath. When the temperature had 'reached 10 C. solid chloral cyanhydrin (4.5 g.) was'added, followed, after standing for five minutes, by theaddition over a period of about 5 minutes of a solution of triethylamine (5.5 cc.) in dioxan (12 cc.). The last additioncaused an exothermic reaction to take place and the temperature was maintained below 30 C. by cooling in an ice-water bath. The, pale brown suspension was allowed to stand overnight at normal temperature and then poured onto ice (100 g.) and water (200 g.). After standing for four hours, the suspension was made acid to Congo redby. the addition of concentrated hydrochloric acid. The dichloracetyl derivative was filtered off and washed with water. The aqueous filtrate was extracted with ethyl acetate and, after concentration to small volume, a little petroleum ether added which caused a further quantity of the dichloracetyl derivative to separate. The yield (6.40 g.) of DL-threo 2-dichloracetamido-l-p-nitrophenylpropane.. l:3-diol' (commonly known as racemic Chloramphenicol) was 99% of theory and it melted at 149-151 C. It was obtained as an almost colourless crystalline solid. 7

Example XVI The triethylamine (5.5 cc.) in dioxan (12 cc.) used in Example XV was replaced by anhydrous sodium carbonate' (2.6 g.). The yield of DL-th'reo 2-dichloracetamido-l-p-nitrophenylpropaue 1:3-diol was not, however, as great as that obtained in Example XV.

Example XVII Chloral cyanhydrin (4.3 g.) was added to dry pyridine (15 cc.) and immediately afterwards DL-threo Z-aminol-p-nitrophenylpropane 1:3-diol (4.2 g.) was added to the cooled solution. The internal temperature rose to 40 C. and the mixture was heated on a steam bath for 15 -minutes. The light brown solution was poured onto water and ice and, after standing for one hour, acidified with concentrated hydrochloric acid. The DL-threo 2-dichloracetamido-l-p-nitrophenylpropane 1:3-diol was filtered off and crystallised from a mixture of ethyl acetate and petroleum ether. The product was identical with that of Example XV.

- tion, a second yield of product.

6 Example XVIII DL-threo 2-amino-l-p-nitrophenylpropane 1:3-diol hydrochloride (2.49 g.) was dissolved in water (15 cc.). Chloral cyanhydrin (2.5 g.) was dissolved in this solution and, after cooling to 0 C., triethylamine (3.0 g.) was added drop by drop over five minutes with shaking between each addition. An oil was deposited 'which solidified after shaking for half an hour. The suspension was allowed to stand for four hours and then made acid to Congo red by the addition of concentrated hydrochloric acid. The DL-threo 2-dichloracetamido-1-pnitrophenylpropane 1:3-diol was filtered off, washed with water and dried. The yield (3.15 g.) was 97% of theory. The product is the same as that of Example XV.

Example XIX A mixture of L-erythro 2-amino-l-p-nitrophenylpropane 1:3-diol hydrochloride (12.6 g.) (M. P. 194-8 C. (a) =+15.8 (c=6% in water)), dry dioxan (65 cc.) and dry triethylamine (6.2 cc.) was allowed to stand at laboratory temperature for one hour. Chloral cyanhydrin (11.8 g.) was added over five minutes and the mixture cooled in an ice bath. Three amounts of triethylamine (5 cc., 5 cc., and 2.5 cc.) were added with good stirring at intervals of five minutes. The slightly brown crystalline magma was allowed to stand at laboratory temperature overnight. The triethylamine hydrochloride was filtered olf and washed with dioxah. The combined filtrates were evaporated to about 50 cc. under reduced pressure and, after cooling, the solid collected and washedthree times with water. The dioxan filtrate and the "aqueous washings were combined and extracted with ethyl acetate to yield, on concentra- The total yield obtained of L-erythro 2-dichloracetamido-l-p-nitrophenylpropane 153-diol, 'M. P.- 178 C. (a) =25.8 (c=4% in acetone),- was 12.8 g. or 78% of theory.

- Example XX 4.24 g. of DL-erythro 2-amino-l-p-nitrophenylpropane 1:3-diol of M. P. '108-109 C. were dissolved in anhydrous dioxan (25 cc.) by heating to 70 C. The solution'was cooled to +10 C. and at this temperature chloral cyanhydrin (4.5 g.) was added. After 5 minutes a solution of anhydrous triethylamine (4.0 g.) in dioxan (12 cc.) was run in, keeping the temperature at about C. The mixture was stirred for 2 hours at ordinary temperature then left to stand overnight. 'The product which crystallised was filtered off and the filtrate evaporated under reduced pressure. The residue of the filtration and the residue of the evaporation were taken up in water (35 cc.), and after acidifying with sulphuric acid and filtering the crude product obtained (6.64 g.) was recrystallised in water. There were" obtained 4.66 g. of'- DL-erythro 2-dichloracetamido-l-p-nitrophenylpropane 1:3-di0l of M. P. 169-171 C. By extraction of the mother liquors a second yield (0.44 g.) was obtained of M. P. 168170 C. I

Example XXI I DL-erythro 2-amino-l-p-nitrophenylpropane 1:3-diol hydrochloride (4.97 g.) were suspended in anhydrous dioxan (25 cc.). Anhydrous triethylamine (2.0 g.) was added and after stirring for 1 hour at about 70 C. the mixture was cooled to 10 C. and treated as in Example II with chloral cyanhydrin (4.5 g.) and anhydrous triethylamine (4.0 g.) in dioxan (12 cc.). A first yield was obtained of 3.84 g. of DL -erythro 2-dich1oracetamido- 1'-p-nitrophenylpropane 1:3-diol, M. P. 167-168 C., and

a second yield 0.19 g.) of P. 162-166 c.

' Example XXII 'DL-erythro Z-amino-l-nitrophenylpropane 1:3-diol (5.3 g.) was dissolved in dry pyridine 25 cc.) and the solution then cooled to 0 C. Chloral cyanhydrin (5.5 g.)

DL erythro 2-amino-l-phenylpropane lz 3-diol (0.4 g.:

M. P. 1"03 C.) was dissolved in dry-dioxan (8.0 cc.) at

50-60 C. and the solution was. thencooled to laboratory temperature. Chloral cyanhydrin (0.6 g.) was added, followedby triethylamine (l.5 cc.). The reaction mixture was cooled during the additions. After standing overnight, the reaction mixture was poured into ice-water (50g) At-first a solution was'obtained but on standinjg for-540' minutes, the product separated in a colourless felt-like mass of crystals. After standing for two hours, the mixture was madeacid to Congo red by'the addition of concentrated hydrochloric acid. The crystals werefilteredoff and dried at 100 C. A further. amount of product was obtained by extracting the filtrate with chloroform. The total yield obtained of DL-erythro Z-dichloracetamido-l-phenylpropane 1:3-diol (M. P. 6- 158 C.) was 0.60 g., or 92% of. theory.

Ext'z'mple XXIV DL-erythro2-amino-1-phenylpropane 1:3-dio1 (1.67 g.) was dissolved in pure hot dioxan (32 cc.), and then the solution cooled in an ice-bath. Solid chloral cyanhydrin (2.5 g.) was added, followed, after "standing for five minutes, by triethylamine (6.0 cc.) added over five minutes. The colourless suspension so formed, was allowed to stand overnight at normal temperature and thenpoured onto ice (50 g.) and water (50* cc.). ,After standing for two hours the suspension was made acid to Congo red by the addition of concentrated hydrochloric acid. The dichloracetyl derivative was'filtered off and washed with water. An improved yield was obtained'by extracting the aqueous filtrate with ethyl acetate. The total yield (2.56 g.) of DL-erythro Z-dichloracetamido-l-phenylpropane 1:3-diol was 92% of theory. It was obtained ascolourless needles.

Example XX V A solution of chloral cyanhydrin (5.64 g.) dissolved indry dioxan (25 cc.) at 10 C. was treated slowly with a .solution of triethylamine (6.87 g.) dissolved in dry dioxan (30 cc.) at such a rate that the temperature did not rise above 15 C. The precipitated triethylamine hydrochloride was filtered ofi and Washed with dry dioxan. To the filtrate was added a solution of DL-erythro 2- arnino-Lp-nitrophenylpropane 1:3-dio1 (5.3 g.) in dry dioxan (250 cc.), and the reaction allowed to proceed atfnormal temperatures overnight. 7

The next day the solution was poured into a large excess of water and the solution made acid to Congo red. The desired product, DL-erythro 2-dichloracetamido-1-pnitrophenylpropane 1:3-diol was extracted with ethyl acetate (6 extractions). After concentration of the ethyl acetate solution to 40 cc., the crude product crystallised on cooling (7.7 g., 95% of theory). Crystallisation of the crude product from dioxan gave the pureproduct, M; P. 176C. 7

Racemic .threo and-erythro-5-amino-4-phenyl-2-methyll:3.-.di0Xan employed as starting materials incertain of the foregoing examples were prepared as follows: benzaldehyde and Z-nitroethahol were condensed together as described by Controulis, Rebstock and Crooks in the Journal of the American Chemical Society of 1949, volume 71, page 2463, and the sodium salt converted to Z-nitro-l-phenylpropane 1:3 diol by means of acetic acid inithe presence of ether. The three and the erythro isomers of 2-nitro-1-phenylpropane 1:3-diol were "separatedby crystallisation. (Bach isomer was converted to the DL-S nitro-4aphenyl-2methyll 3 dioxan by treatment of the ethereal solution 'of the diol with acetaldehyde in the presence of an acidcatalyst such; as p-toluene sulphonic acid. Catalytic reduction of the threo and erythro nitro-dioxans gave the desired amines.

I claim: 1 Process for theproduction of a compound'of formula,

'(|)R1'NH'.GOCHC12 Ra" on'-en-omon= in which Ri'and R2 are members of the class consisting of hydrogen atoms and further members wherein R1 and R2 together form a '-CH(lower a'lkyl)-group"an*d R is a member of the class 'consistingof H and N02, which comprises reacting an amine of formula,

on. NH:

'11. C.H-'CH"CHO'R with a dichloracetylatingagent 'of the class consisting of (1) at least 'o'ne'equivalent of chloral eyanhydrin, (2) at least one equivalent of chloral and less than one equivalent of an alkali metalcyanide'and (3)at least one equivalent of chloralhydrate' and less than 'one equivalent of an alkali metal cyanideinan alkaline reaction'medium at a temperature below about i C.

2. Process for the prdduc'tionof a compound of formula,

remakes-c1.

which comprises reacting an amine of formula,

OH NH:

with at least one equivalent for chloral'hydrate in the presence of less than one equivalent 'of an'alkali metal cyanide in an alkaline reaction-medium at a temperature below about 100 C.

31. Process for'the production of a compound of formu a,

I l 1H uno-onon umO-orr-oH-bmorr which comprises "reacting an amine of formula,

on h m: NOz-C HCH-CH2UH with at least one equivalent of chloral hydrate in the presence of less than one equivalent of an alkali metal cyanide at a temperature between 60 and 100 C. in an aqueous re'actionmedium containing at least one equivalent of an inorganic base.

4. Process for the production of 'DL erythro-2-dichloracetamido-l-p-nitrophenylpropane-l,3-diol which comprises reacting DL-erythro-Z-arnino-l-p-nitrophenylpropane'l,3 -diol with atleast one equivalent of chloral hydrate in thepres'enceof less than'oneequivalent of sodium cyanide at 'a temperature 100 C. in 'ah aqueous reaction mediium containing'at least oneequivalentof magnesium 0x1 e.

5. Process for theproduction of a compound of formula,

9 10 which comprises reacting an amine of formula, 7. Process for the production of DL-threo-Z-dichlor- OH NH2 acetamido-l-p-nitrophenylpropane-1,3-diol which com- 1 prises reacting DL-threo-Z-amino-l-p-nitrophenylpropane- NOrO OH H OHOH 1,3-diol with at least one equivalent of chloral cyan- 5 hydrin at a temperature between 0 and 25 C. in angig gl z gi igg ggi g f ggggi ig gg i gg s gg hydrousdioxane containing at least one equivalent of tri- 25 C ethylamme.

61. Process for the production of a compound of for- References Cited inthe of this Patent mu O UNITED STATES PATENTS 1% 2,483,884 Crooks et a1. Oct. 4, 1949 E E TCHCI 2,483,885 Crooks et a1. Oct. 4, 1949 0 FOREIGN PATENTS which comprises reacting an amine of formula, 503,348 Belgium June 15, 1951 11 NH, OTHER REFERENCES NOPC CHCHCH2OH Irving: J. Chem. Soc. (London) 1936, pp. 797-801. Beilstein: Handbuch Organischen Chemie 4th ed.,

with at least one equivalent of chloral cyanhydrin at a VOL 3 1921 2 g temperature between 0 and C. in an anhydrous i i hi c f Org, Cyanogen CORP organic solvent containing at least one equivalent of a pounds 1947 1g7 1g3 tertiary organic amine. 

1. PROCESS FOR THE PRODUCTION OF A COMPOUND OF FORMULA,
 2. PROCESS FOR THE PRODUCTION OF A COMPOUND OF FORMULA, 